Management of Crohn’s Disease— A Practical Approach

PRACTICAL THERAPEUTICS

Management of Crohn's Disease-- A Practical Approach

DOUG KNUTSON, M.D., GREG GREENBERG, M.D., and HOLLY CRONAU, M.D. Ohio State University College of Medicine and Public Health, Columbus, Ohio

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract that affects up to 480,000 persons in the United States. Symptoms include abdominal pain, diarrhea, fever, malaise, and arthralgias, and cause considerable morbidity. Speculation about genetic, environmental, dietary, infectious, and immunologic etiologies has led to treatment modalities directed at each theoretic cause, but therapy guidelines are determined by the severity of disease. Use of salicylates and/or antibiotics can be effective in mild to moderate disease, while steroids are the accepted therapy for more severe active disease. Azathioprine and other immunosuppresant drugs can be used as adjunctive therapy for active Crohn's disease and may help to maintain remission. Infliximab, an antibody to human tumor necrosis factor alpha, has proved successful in the treatment of severe refractory disease and generally causes only mild side effects. Therapy for Crohn's disease must involve treating comorbid conditions to improve the quality of life of patients. (Am Fam Physician 2003;68:707-14,717-8. Copyright? 2003 American Academy of Family Physicians.)

O A patient informa-

tion handout on Crohn's disease, written by the authors of this article, is provided on page 717.

Members of various medical faculties develop articles for "Practical Therapeutics." This article is one in a series coordinated by the Department of Family Medicine at Ohio State University College of Medicine and Public Health, Columbus. Guest editor of the series is Doug Knutson, M.D.

See page 621 for definitions of strength-ofevidence levels.

Crohn's disease is a chronic, relapsing inflammatory disorder of the alimentary canal with involvement anywhere from the mouth to the anus. Manifestations of the disease cause considerable morbidity and social cost. This article will focus on the evaluation and management of Crohn's disease by the family physician.

Epidemiology, Etiology, and Pathophysiology

Crohn's disease affects approximately 380,000 to 480,000 persons in the United States.1 Although it may occur at any age, the incidence is bimodal with a peak in the third decade of life and a smaller peak in the fifth decade.2 The etiology of Crohn's disease is unknown, but suggested possibilities include genetic, environmental, immunologic, and infectious causes. Theories of a genetic basis for the disease are supported by family history and prevalence information, but no clear-cut pattern of inheritance has been established.

The incidence of Crohn's disease differs across racial and ethnic boundaries. It is more common in whites than in blacks, in women than in men, and in Jewish than in non-Jewish

persons.3 Environmental factors must play a role in the development of Crohn's disease, because while the disease is uncommon in African blacks, U.S. blacks have an incidence similar to that of whites.2 Also, there is some association with diet, and the disease affects more smokers than expected.2,3

While etiologic evidence suggests a complex interplay between many factors, pathophysiologically, Crohn's disease involves an immune system dysfunction. An imbalance in local mucosal production of pro-inflammatory cytokines over anti-inflammatory cytokines is theorized to cause the well-demarcated, discontinuous, transmural, ulcerative lesions characteristic of the disease.4 Clinical features of Crohn's disease are listed in Table 1.5

Diagnosis

A diagnosis of Crohn's disease should be considered in any patient who presents with chronic or nocturnal diarrhea, abdominal pain, bowel obstruction, weight loss, fever, or night sweats.5 However, symptoms of Crohn's disease are often insidious, and diagnosis can be difficult. Patients may have intermittent symptoms with varying periods of remission. Over time, symptomatic periods may increase in frequency and severity.

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With the appropriate clinical presentation, the diagnosis of Crohn's disease can be suggested by radiography, but should be confirmed by endoscopy and biopsy when possible.

Crampy, intermittent pain is the most common symptom of Crohn's disease. The pain may evolve into a constant dull ache as the disease progresses. Diarrhea is present in 85 percent of patients; other symptoms include hematochezia, fever, weight loss, malaise, nausea, and arthralgias. The differential diagnosis depends on the presenting complaint, and includes acute appendicitis, small bowel obstruction, ulcerative colitis, irritable bowel syndrome, malabsorption syndromes, infectious or ischemic colitis, neoplasia, hemorrhoids, and diverticular disease. When joint manifestations or fatigue predominates, the differential is expanded further.6

Results from laboratory evaluation can be normal, but electrolyte abnormalities may occur secondary to diarrhea. Anemia also can be caused by malabsorption of vitamin B12, blood loss, or the effect of inflammation on the bone marrow. Patients may also have an

TABLE 1

Clinical Features of Crohn's Disease

Common complaints Abdominal pain Diarrhea Fever Fatigue Rectal bleeding Weight loss Anorexia Nausea

Common physical examination findings Abdominal tenderness Palpable mass Guaiac-positive stool

Common laboratory and radiographic findings Mild anemia Mild leukocytosis Elevated erythrocyte sedimentation rate Small bowel involvement Fistulas Strictures

Information from Hanauer SB, Sanborn W. The management of Crohn's disease in adults. Am J Gastroenterol 2001;96:635-43.

TABLE 2

Extra-intestinal Manifestations of Crohn's Disease

Joint manifestations (25 percent) Arthralgia Arthritis

Skin manifestations (15 percent) Erythema nodosum Pyoderma gangrenosum Aphthous ulcers of the mouth

Ocular manifestations (5 percent) Episcleritis Uveitis Recurrent iritis

Information from Hanauer SB, Sanborn W. The management of Crohn's disease in adults. Am J Gastroenterol 2001;96:635-43.

elevated erythrocyte sedimentation rate. With the appropriate clinical presentation, the diagnosis can be suggested by radiography, but should be confirmed by endoscopy and biopsy when possible. When the colon is involved, endoscopy reveals the characteristic ulcers with normal surrounding mucosa. Radiographic studies of the small bowel may show luminal narrowing, nodular contour, linear ulcers, or fistulas. Computed tomography (CT) may help to identify abscesses and other complications.2

Management of Crohn's Disease The medical management of Crohn's disease

is based on the location and severity of disease and extra-intestinal complications (Table 2).5 Therapy has two goals--to treat the acute disease flare-ups and to maintain remission. Because no "gold standard" exists to define disease severity, working definitions of disease activity have been established to help guide therapy. These definitions are listed and defined in Table 3,5 while the various treatment options for Crohn's disease are provided in Table 4.5

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TABLE 3

Working Definitions of Crohn's Disease Activity

Mild to moderate disease The patient is ambulatory and able to take oral alimentation. There is no dehydration, high fever, abdominal tenderness, painful mass, obstruction, or weight loss of more than 10 percent. Moderate to severe disease Either the patient has failed treatment for mild to moderate disease OR has more pronounced symptoms including fever, significant weight loss, abdominal pain or tenderness, intermittent nausea and vomiting, or significant anemia. Severe fulminant disease Either the patient has persistent symptoms despite outpatient steroid therapy OR has high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess. Remission The patient is asymptomatic OR without inflammatory sequelae, including patients responding to acute medical intervention.

Information from Hanauer SB, Sanborn W. The management of Crohn's disease in adults. Am J Gastroenterol 2001;96:635-43.

TABLE 4

Treatment Options in Crohn's Disease

Treatment

Examples

Results

Problems with use

Salicylates

Mesalamine (Rowasa), sulfasalazine (Azulfidine)

Beneficial for mild to moderate Inconclusive maintenance of remission, active disease, proctosigmoiditis risk of GI bleed or upset

Corticosteroids

Oral prednisone, budesonide (Entocort), IV preparations

Beneficial for moderate to severe active disease, generally accepted therapy

Side effects from long-term use, budesonide not approved for use in the United States

Antibiotics

Metronidazole (Flagyl), ciprofloxacin (Cipro)

Beneficial in treatment of mild to moderate disease, maintenance of remission

Specific antibiotic side effects include metallic taste in mouth, disulfiram effects, GI upset, peripheral neuropathy

Immunosuppressants

Azathioprine (Imuran), 6-mercaptopurine (Purinethol), methotrexate (Rheumatrex), cyclosporine (Sandimmune), others

Beneficial in treatment and in maintenance of remission, beneficial to decrease steroid use

Questionable risks for neoplasia, leukopenia (requires blood monitoring)

Antibody to human tumor necrosis factor alpha

Infliximab (Remicade)

Significant improvement when compared with placebo

Costly, IV administration, mild infusion reactions might be seen

GI = gastrointestinal; IV = intravenous. Information from Hanauer SB, Sanborn W. The management of Crohn's disease in adults. Am J Gastroenterol 2001;96:635-43.

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Because the natural history of Crohn's disease is characterized by a variable course with spontaneous flare-ups and remissions, it is difficult to prove therapeutic benefit from intervention. However, based on evidence from therapeutic trials, guidelines for the management of Crohn's disease have been developed. An algorithm for the medical management of Crohn's disease is provided in Figure 1.4

Mild to Moderate Disease

Mild to moderate Crohn's disease can be treated with a salicylate preparation, and in patients who are unresponsive, an antibiotic may help.5 Response to therapy should be

evaluated after several weeks; patients who do not respond should be treated for moderate to severe disease or with alternative therapy.

The salicylates include mesalamine (Rowasa) and sulfasalazine (Azulfidine). In its various preparations, mesalamine can be released in the stomach, duodenum, ileum, and colon (Pentasa), or primarily in the terminal ileum and colon (Asacol).7 Both mesalamine preparations are generally more effective than placebo in improving disease symptoms and inducing remission in patients with active Crohn's disease; however, greater benefit is seen in patients with ileitis versus colitis or ileocolitis.8 The dosage of oral mesalamine is 3.2 to 4 g per day.

Medical Management of Crohn's Disease

Mild to moderate disease (ambulating and tolerating oral intake)

Moderate to severe disease (weight loss, abdominal pain, or vomiting)

Severe disease (high fever, guarding, or intractable vomiting)

Salicylate therapy

Prednisone with rapid taper

Intravenous steroids with rapid taper*

Metronidazole (Flagyl) or ciprofloxacin (Cipro)

No Effective? Yes

No Effective?

Yes

No

Infliximab (Remicade)

Effective?

Yes

Yes Effective?

No

Mesalamine (Rowasa) for maintenance

Treat as moderate or severe.

No

Maintain remission?

Consider immunosuppressant.

Yes

Continue treatment.

Yes

No

Maintain remission?

Consider methotrexate (Rheumatrex).

*--Rule out infection before starting intravenous steroids or infliximab.

FIGURE 1. Algorithm for the medical management of Crohn's disease.

Adapted with permission from Wall GC, Heyneman C, Pfanner TP. Medical options for treating Crohn's disease in adults: focus on antitumor necrosis factor-alpha chimeric monoclonal antibody. Pharmacotherapy 1999;19:1148.

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In a study9 conducted in 1979, sulfasalazine demonstrated benefits over placebo, with approximately 50 percent of patients enrolled in large clinical trials achieving clinical remission. The suggested dosage of sulfasalazine is 3 to 6 g per day. Sulfasalazine does not have significant benefit in maintaining remission9,10; mesalamine may maintain remission at higher dosages and in some subsets of patients.

In the treatment of mild to moderate active Crohn's disease, antibiotic therapy may be an acceptable alternative. Metronidazole (Flagyl) in a dosage of 10 to 20 mg per kg per day has demonstrated benefit in the treatment of ileocolitis and colitis, with most patients reporting clinical improvement and more than one half achieving remission.11 [Evidence level A: randomized controlled trial (RCT)] In addition to a metallic taste, disulfiram-like effect, and gastrointestinal upset, long-term use of metronidazole is known to cause peripheral neuropathy, and patients should be monitored.

Ciprofloxacin (Cipro) in a dosage of 1 g per day has also decreased disease activity similar to that of mesalamine, 4 g per day.12 [Evidence level B: lower quality RCT] In a study13 of patients with active Crohn's disease, no difference was noted between patients treated with a combination of ciprofloxacin and metronidazole, and those treated with prednisone at 12 weeks.13

Moderate to Severe Disease

Patients with Crohn's disease that is classified as moderate to severe should be treated with steroids until symptoms resolve and weight loss is reversed. The immunomodulators azathioprine (Imuran) and mercaptopurine (Purinethol) may be used, but full response may not be achieved for several months. Infliximab (Remicade) may be an alternative if corticosteroids are ineffective or contraindicated.

Oral corticosteroids have been the mainstay for treating moderate to severe active Crohn's

disease. Their effectiveness in inducing remission has long been known, and their onset of action is more rapid than that of salicylates. While studies have not revealed a generally accepted dosage schedule, 50 to 70 percent of patients receiving the equivalent of prednisone 40 mg daily over eight to 12 weeks have been shown to achieve a clinical response.9

After clinical response, dosage is tapered according to rapidity and completeness of response, often requiring months to discontinue.14 Dosages can be tapered by 5 to 10 mg weekly until 20 mg, and by 2.5 to 5 mg weekly thereafter.14 Steroids have no role in maintaining remission. In addition, concerns regarding the long-term side effects of steroid use, including diabetes mellitus, osteoporosis, and adrenal suppression, limit their long-term use. Prednisone enemas may be helpful in proctosigmoid disease but are not as effective as salicylate preparations.

Budesonide (Entocort) is a potent corticosteroid with poor systemic absorption because of a 90 percent first-pass metabolism, apparently resulting in fewer side effects and less adrenal suppression than prednisone.15,16 Budesonide is superior to mesalamine and placebo in patients with active Crohn's disease17 and is comparable to oral prednisolone.18

The role of immunomodulators in Crohn's disease continues to be studied. Immunosuppressants, specifically azathioprine and 6-mercaptopurine, have demonstrated adjunctive benefits to use of steroids in adults,19,20 but they may take up to four months to demonstrate benefit.20 These medications should be considered in patients who are steroid dependent or resistant to other forms of treatment.20 [Evidence level A: Systematic review of RCTs] Immunosuppressants have allowed reduction in steroid dosages with maintenance of remission after inductive therapy. Despite concerns, there is no suggestion of an increased risk for neoplasia; however, one patient developed a brain lymphoma generally seen in immunocompromised patients.21

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